scholarly journals The extinction of conditioned fear: structural and molecular basis and therapeutic use

2006 ◽  
Vol 29 (1) ◽  
pp. 80-85 ◽  
Author(s):  
Martín Cammarota ◽  
Lia R M Bevilaqua ◽  
Mônica R M Vianna ◽  
Jorge H Medina ◽  
Iván Izquierdo

OBJECTIVE: Through association, a large variety of stimuli acquire the property of signaling pleasant or aversive events. Pictures of a wedding or of a plane disaster may serve as cues to recall these events and/or others of a similar nature or emotional tone. Presentation of the cues unassociated with the events, particularly if repeated, reduces the tendency to retrieve the original learning based on that association. This attenuation of the expression of a learned response was discovered by Pavlov 100 years ago, who called it extinction. In this article we review some of the most recent findings about the behavioral and biochemical properties of extinction. RESULTS AND DISCUSSION: It has been shown that extinction is a new learning based on a new link formed by the cues and the absence of the original event(s) which originated the first association. Extinction does not consist of the erasure of the original memory, but of an inhibition of its retrieval: the original response reappears readily if the former association is reiterated, or if enough time is allowed to pass (spontaneous recovery). Extinction requires neural activity, signaling pathways, gene expression and protein synthesis in the ventromedial prefrontal cortex and/or basolateral amygdala, hippocampus, entorhinal cortex and eventually other areas. The site or sites of extinction vary with the task. CONCLUSIONS: Extinction was advocated by Freud in the 1920's for the treatment of phobias, and is used in cognitive therapy to treat diseases that rely on conditioned fear (phobias, panic, and particularly posttraumatic stress disorder). The treatment of learned fear disorders with medications is still unsatisfactory although some have been shown useful when used as adjuncts to behavioral therapy.

2018 ◽  
Vol 32 (8) ◽  
pp. 932-942 ◽  
Author(s):  
Mohammad Nasehi ◽  
Saman Shahbazzadeh ◽  
Mohaddeseh Ebrahimi-Ghiri ◽  
Mohammad-Reza Zarrindast

The basolateral amygdala (BLA) is a major target and modulator of stress and has a critical role in the neural circuitry presenting learned fear behaviors. On the other hand, both the endocannabinoid and noradrenergic systems may be involved in regulating the stress responses, fear, and anxiety. Considering the aforementioned, we have investigated the involvement of the BLA β1-adrenoceptors in conditioned fear responses induced by ACPA, a CB1 receptor (CB1R) agonist. In adult male NMRI mice, freezing responses to context and cue were measured using a Pavlovian fear conditioning apparatus. Pre-training intra-BLA microinjection of xamoterol (0.01 and 0.02 µg/mouse), a partial β1-adrenoceptor agonist, or atenolol (0.5 µg/mouse), a β1-adrenoceptor antagonist, decreased freezing behavior, which suggests an impairment of contextual and auditory fear retrieval. Similar results were found with pre-training intraperitoneal administration of ACPA (0.5 mg/kg). A sub-threshold dose of xamoterol, infused into the BLA, decreased ACPA (0.005 and 0.05 mg/kg) effect on both memories, while atenolol increased ACPA response to the context at the middle dose and decreased ACPA response to the tone at the lower dose. It can be concluded that the blockade of BLA β1-adrenoceptors differentially affects ACPA response on the contextual and auditory conditioned fear memories.


2004 ◽  
Vol 76 (3) ◽  
pp. 573-582 ◽  
Author(s):  
Martín Cammarota ◽  
Daniela M. Barros ◽  
Mónica R.M. Vianna ◽  
Lia R.M. Bevilaqua ◽  
Adriana Coitinho ◽  
...  

Memory is measured by measuring retrieval. Retrieval is often triggered by the conditioned stimulus (CS); however, as known since Pavlov, presentation of the CS alone generates extinction. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response is to stay in the safe area. In IA, retrieval is measured without the US, as latency to step-down from the safe area (i.e., a platform). Extinction is installed at the moment of the first unreinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is behaviorally and biochemically necessary for the generation of extinction, this last process constitutes a new learning secondary to the unreinforced expression of the original trace.


2010 ◽  
Vol 10 (S1) ◽  
Author(s):  
Ramon O Tasan ◽  
Dilip Verma ◽  
Herbert Herzog ◽  
Günther Sperk

2021 ◽  
Vol 396 ◽  
pp. 112913
Author(s):  
Olena Bukalo ◽  
Mio Nonaka ◽  
Chase A. Weinholtz ◽  
Adriana Mendez ◽  
William W. Taylor ◽  
...  

2009 ◽  
Vol 101 (3) ◽  
pp. 1629-1646 ◽  
Author(s):  
Guoshi Li ◽  
Satish S. Nair ◽  
Gregory J. Quirk

The basolateral amygdala plays an important role in the acquisition and expression of both fear conditioning and fear extinction. To understand how a single structure could encode these “opposite” memories, we developed a biophysical network model of the lateral amygdala (LA) neurons during auditory fear conditioning and extinction. Membrane channel properties were selected to match waveforms and firing properties of pyramidal cells and interneurons in LA, from published in vitro studies. Hebbian plasticity was implemented in excitatory AMPA and inhibitory GABAA receptor-mediated synapses to model learning. The occurrence of synaptic potentiation versus depression was determined by intracellular calcium levels, according to the calcium control hypothesis. The model was able to replicate conditioning- and extinction-induced changes in tone responses of LA neurons in behaving rats. Our main finding is that LA activity during both acquisition and extinction can be controlled by a balance between pyramidal cell and interneuron activations. Extinction training depressed conditioned synapses and also potentiated local interneurons, thereby inhibiting the responses of pyramidal cells to auditory input. Both long-term depression and potentiation of inhibition were required to initiate and maintain extinction. The model provides insights into the sites of plasticity in conditioning and extinction, the mechanism of spontaneous recovery, and the role of amygdala NMDA receptors in extinction learning.


2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Amanda C. Alvarez-Dieppa ◽  
Kimberly Griffin ◽  
Sheridan Cavalier ◽  
Christa K. McIntyre

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.


2020 ◽  
Author(s):  
Belinda P. P. Lay ◽  
Audrey Pitaru ◽  
Nathan Boulianne ◽  
Guillem R. Esber ◽  
Mihaela D. Iordanova

Understanding how learned fear can be reduced is at the heart of treatments for anxiety disorders. Tremendous progress has been made in this regard through extinction training in which an expected aversive outcome is omitted. However, current progress almost entirely rests on this single paradigm, resulting in a very specialized knowledgebase at the behavioural and neural level of analysis. Here, we used a paradigm-independent approach to show that different methods that lead to reduction in learned fear are dissociated in the cortex. We report that the infralimbic cortex has a very specific role in fear reduction that depends on the omission of aversive events but not on overexpectation. The orbitofrontal cortex, a structure generally overlooked in fear, is critical for downregulating fear when fear is inflated or overexpected, but not when an aversive event is omitted.


Sign in / Sign up

Export Citation Format

Share Document